Next-Generation off-the-shelf CAR γδ T cells for ovarian cancer immunotherapy

Dr. Conejo-Garcia’s vision is to transform the outcome of patients with ovarian cancer by exploiting two unique properties of the immune system: specificity and memory. To this end, his laboratory investigates spontaneous antitumor immune responses, including both cellular and humoral (antibody-mediated) immunity, and identifies novel vulnerabilities in patient tumor specimens. This work aims to develop more effective, biologically guided immunotherapies. Key areas of focus include the discovery of previously unidentified cell surface antigens suitable for targeting with off-the-shelf cellular therapies that use subsets of gamma delta T cells and antibody-drug conjugates, as well as the development of next-generation anticancer vaccines. The ultimate objective is to advance these therapeutic candidates into clinical trials, in collaboration with physicians at Duke.

Ovarian cancer is one of the deadliest cancers because it often resists treatment and actively suppresses the immune system. Current cell therapies are difficult to manufacture, expensive, and frequently fail to persist or work effectively in this hostile tumor environment. This project aims to develop a new, affordable, “off-the-shelf” immune cell therapy that can be prepared in advance and given to ma5Title + textaddexpandmore-dots Title Textparagraphheaderheader-2header-3bolditaliclinkuloltableundoredoOvarian cancer is one of the deadliest cancers because it often resists treatment and actively suppresses the immune system. Current cell therapies are difficult to manufacture, expensive, and frequently fail to persist or work effectively in this hostile tumor environment. This project aims to develop a new, affordable, “off-the-shelf” immune cell therapy that can be prepared in advance and given to many patients without the need to manufacture a custom product for each individual.We will use a specialized type of immune cell, called gamma delta (γδ) T cells, that naturally migrate into tumors and recognize stressed or cancerous cells even without genetic engineering. These cells will be obtained from donated umbilical cord blood, allowing us to produce enough treatment from a single donation for many patients. We will equip these cells with a redesigned cancer-targeting receptor that uses a signaling system intended to make the cells more powerful, longer-lasting, and resistant to exhaustion inside tumors.To improve safety, we will target a marker called citrullinated vimentin, which appears on the surface of cancer cells and tumor-supporting cells but not on healthy tissues. We will also modify the cells so they are less visible to the patient’s immune system, allowing them to survive longer after infusion.The goals of this project are to demonstrate that these engineered cells are effective, safe, long-lived, and can be manufactured under clinical standards. This work will support future clinical trials and may establish a broadly applicable, lower-cost cancer cell therapy platform."The Lotus Award will enable our team to complete a GMP-compliant protocol for the expansion and transduction of gamma delta (γδ) T cells derived from the extensive cord blood repository—comprising over 35,000 units—available to us at Duke University. We anticipate that this work will provide a robust biological and manufacturing rationale for subsequent clinical trials. Ultimately, our goal is to render CAR T cell therapies substantially more affordable, logistically accessible for timely patient intervention, and—most critically—efficacious for individuals with recurrent, chemoresistant ovarian carcinoma." CTA typeExternalFile CTA label CTA URL ny patients without the need to manufacture a custom product for each individual.

We will use a specialized type of immune cell, called gamma delta (γδ) T cells, that naturally migrate into tumors and recognize stressed or cancerous cells even without genetic engineering. These cells will be obtained from donated umbilical cord blood, allowing us to produce enough treatment from a single donation for many patients. We will equip these cells with a redesigned cancer-targeting receptor that uses a signaling system intended to make the cells more powerful, longer-lasting, and resistant to exhaustion inside tumors.

To improve safety, we will target a marker called citrullinated vimentin, which appears on the surface of cancer cells and tumor-supporting cells but not on healthy tissues. We will also modify the cells so they are less visible to the patient’s immune system, allowing them to survive longer after infusion.

The goals of this project are to demonstrate that these engineered cells are effective, safe, long-lived, and can be manufactured under clinical standards. This work will support future clinical trials and may establish a broadly applicable, lower-cost cancer cell therapy platform.

Dr. Conejo-Garcia is a professor of Immunology at Duke University School of Medicine and co-leader of the Immuno-Oncology Program at the Duke Cancer Institute. His research program focuses on investigating antitumor immunity to develop immunotherapies that reverse the prognosis of patients with advanced ovarian cancer and other malignancies.

Dr. Conejo-Garcia pursued his medical degree, PhD, and clinical residency in Spain. He then worked as a research3Quoteaddexpandmore-dots Quote Captioner in Bern (Switzerland) and Hannover (Germany), before joining George Coukos' team at the University of Pennsylvania, contributing to the discovery of the role of T cell responses in ovarian cancer. He then joined the faculty of Dartmouth College, before returning to the UPenn campus to lead the Tumor Microenvironment and Metastasis Program at The Wistar Institute. In 2016 he was recruited by Moffitt Cancer Center, to chair the Department of Immunology. He was later recruited as a Duke Science and Technology Scholar at Duke University, to develop anti-cancer immunotherapies in collaboration with physician-scientists in the Center for Cancer Immunotherapy at Duke. His current research focuses on developing immunotherapies that target the interface between innate (γδ) and adaptive (αβ) T and B lymphocytes, including the clinical testing of novel cellular therapies, and novel tumor cell-penetrating antibodies.

"The Lotus Award will enable our team to complete a GMP-compliant protocol for the expansion and transduction of gamma delta (γδ) T cells derived from the extensive cord blood repository—comprising over 35,000 units—available to us at Duke University. We anticipate that this work will provide a robust biological and manufacturing rationale for subsequent clinical trials. Ultimately, our goal is to render CAR T cell therapies substantially more affordable, logistically accessible for timely patient intervention, and—most critically—efficacious for individuals with recurrent, chemoresistant ovarian carcinoma."